Many diverse studies have demonstrated the potential of delta opioid receptor agonists and antagonists as analgesics and as medications for the treatment and prevention of cocaine and narcotic abuse. We recently reported (+)-4-[(alphaR)-alpha-{(2S,5R)-4-allyl-2,5-dimethyl-1- piperazinyl}-3-methoxybenzyl]-N,N-diethylbenzamide (SNC80) as a novel nonpeptidic delta receptor agonist and explored the structure-activity relationships (SAR) of a series of related derivatives. We have found that delta binding activities and selectivity showed little change when the 3-methoxy group in SNC80 was removed or replaced by the other substituents, whereas the N,N-diethylbenzamide group is important for interaction with the delta receptor. Extensive modification of the piperazine nucleus led to the synthesis of a new series of N,N- diethyl(alpha-piperazinylbenzyl)benzamides, N,N-diethyl(alpha- piperidinyl or piperidinylidenebenzyl)benzamides and related derivatives. Several compounds bound strongly to the delta receptor with Ki values in the low nanomolar range. On the other hand, the binding affinities of these compounds for the mu and kappa receptors were negligible, indicating excellent delta opioid receptor subtype selectivity ranging as high as 4500 fold. The two nitrogen atoms on the piperazine nucleus showed different SAR in the interaction of this series of compounds at the delta receptor. Nitrogen N-4 appears to be an important structural element and is essential for electrostatic interaction, while N-1 seems to be unnecessary for recognition at the delta receptor.We have continued the design, chemical synthesis and biological study of new drugs as potential research tools and medications for the treatment and prevention of opiate, cocaine, methamphetamine and cannabinoid abuse. These studies resulted in new oxygenated derivatives of GBR 12909 as ultra long acting cocaine treatment agents. A single dose of one of these agents prevents self- administration of cocaine by rhesus monkeys for about one month. Other advances include: identification of a new class of drugs which act on the cannabinoid receptor subtypes; discovery of a new series of 4- phenolic delta opioid receptor ligands; and the development of an expedient chemical synthesis of 9-keto-2-methyl-5-(substituted phenyl)morphans. Finally, our synthetic studies have afforded a simple, practical methodology for the direct oxidation of codeinone to 14- hydroxycodeinone. The latter compound is a centrally important intermediate in the manufacturing process of 14-hydroxy opiate agonists for the treatment of pain and narcotic antagonists which are valuable drugs for the treatment of opioid abuse, opioid overdose and alcohol abuse. This novel nonchromatographic methodology is thus highly significant as it simplifies and shortens the synthesis of opium derived drugs essential for the practice of modern medicine. - GBR12909 cocaine treatment medications delta opioids SNC80 14-hydroxycodeinone, synthesis